The present invention relates to a series of compounds which are characterised by a 2-[2-(substituted phenyl-oxy, thio or methyl)-1-methylethyl]aminoethanol structure and which have valuable anti-diabetic and anti-obesity activities; in addition, they are capable of treating or preventing hyperlipemia and hyperglycemia and, by inhibiting the action of aldose reductase, they can also be effective in the treatment and prevention of complications of diabetes. They are also effective in the treatment and prophylaxis of obesity-related hypertension and osteoporosis. The invention also provides processes for preparing the compounds of the present invention, as well as methods and compositions using them.
A number of compounds of this general type is known, and some have been disclosed to have anti-diabetic and/or anti-obesity activity. The known compounds which are structurally related to the compounds of the present invention may be represented by the general formula (A): ##STR2##
For example, D. T. Collin et al. [J. Med. Chem., 13, 674-680 (1970)] disclose compounds in which Q represents, inter alia, an isopropyl group, a t-butyl group or a 2-phenyl-1-methylethyl group, and at least one of R.sup.A1, R.sup.A2 and R.sup.A3 represents a hydrogen atom, and the other two of R.sup.A1, R.sup.A2 and R.sup.A3 represent, for example, hydroxy groups, alkoxy groups, carboxy groups (or esterified carboxy groups) or hydroxymethyl groups. These compounds are said to have an agonistic activity against the .beta.-adrenergic receptors, and are not disclosed as having the same kinds of activities as do the compounds of the present invention.
UK Patent Specification No. 1 551 260 also discloses that compounds represented by the general formula (A), but in which Q represents a phenylaminoethyl group, have the same activity.
UK Patent Specification No. 1 200 886 also discloses compounds represented by the general formula (A), but in which Q represents a hydroxybenzyl, alkoxybenzyl or 2-phenoxy-1-methylethyl group, and these compounds are also alleged to have a p-adrenergic stimulant and blocking activity.
European Patent Publication No. 6735 also discloses a series of compounds of formula (A) in which Q represents a group of formula (B): ##STR3## wherein R.sup.A4 represents a carboxy group or a salt thereof, an alkoxycarbonyl group having from 2 to 5 carbon atoms or an alkylcarbamoyl group having from 2 to 5 carbon atoms; R.sup.A5 represents a hydrogen, chlorine or fluorine atom, a methyl group, a methoxy group, a hydroxy group, a carboxy group or a salt thereof, an alkyloxycarbonyl group having from 2 to 5 carbon atoms or an alkylcarbamoyl group having from 2 to 5 carbon atoms; R.sup.A6 represents a hydrogen atom, or a methyl,., ethyl or propyl group; R.sup.A7 represents a hydrogen atom, or a methyl, ethyl or propyl group; X.sup.A represents an oxygen atom or a single bond; and Y.sup.A represents an alkylene group having from 1 to 6 carbon atoms or a single bond, and these are said to have anti-hyperglycemia and anti-obesity activities.
European Patent Publication No. 21 636, which is currently thought to represent the closest prior art to the present invention, discloses compounds having the general formula (A) in which Q represents a group of formula (B), and in which: R.sup.A1 and R.sup.A2 each represents a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group or a trifluoromethyl group, and R.sup.A1 and R.sup.A2 may be the same or different; R.sup.A3 represents a hydrogen atom; R.sup.A4 represents a hydroxy group or a lower alkyl group substituted with a lower alkoxy or lower acyloxy group; R.sup.A5 represents a hydrogen atom; R.sup.A6 and R.sup.A7 each represents a hydrogen atom or a methyl group, and R.sup.A6 and R.sup.A7 may be the same or different; X.sup.A represents an oxygen atom or a single bond; and Y.sup.A represents a methylene or ethylene group. These are also said to have anti-hyperglycemia and anti-obesity activity. Certain of the compounds of the present invention are a selection from those disclosed in this document and have the advantages that they have little effect on the receptors of the central nervous system, such as the muscarine, N-methyl-D-aspartate and serotonin (5-HT.sub.1, 5-HT.sub.2 and 5-HT.sub.3) receptors. They also have no effect on the cardiovascular system because they have no inotropic activity (right atrium) or chronotropic activity (right atrium). As a result, the compounds of the present invention have far fewer side effects and can thus be expected to find a wider range of practical uses.
European Patent Publication No. 25 331 discloses compounds having the general formula (A), in which Q represents a group of formula (C): ##STR4## and R.sup.A1, R.sup.A2 and R.sup.A3 are the same or different and each represents a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group; R.sup.B1, R.sup.B2, R.sup.B3 and R.sup.B4 each represents a hydrogen atom or a lower alkyl group, and R.sup.B1, R.sup.B2, R.sup.B3 and R.sup.B4 may be the same or different; R.sup.B5 represents a carboxy group, a lower alkyl ester thereof or a group of formula --CONHR.sup.B6 (in which R.sup.B6 represents a hydrogen atom or a lower alkyl group); and Y.sup.B represents an alkylene group having 1 or 2 carbon atoms. These are said to have anti-hyperglycemia and anti-obesity activity.
U.S. Pat. No. 4,338,333 discloses that compounds having the general formula (A) in which Q represents a group of formula (B) and R.sup.A1 represents a hydrogen or halogen atom, or a hydroxy, hydroxymethyl or trifluoromethyl group; R.sup.A2 and R.sup.A3 are the same or different and each represents a hydrogen or halogen atom or a hydroxy group; R.sup.A6 and R.sup.A7 are the same or different and each represents a hydrogen atom or a methyl group; R.sup.A4 represents a hydrogen atom; X.sup.A represents an oxygen atom or a single bond; Y.sup.A represents a methylene or ethylene group; and R.sup.A8 represents a group --O--Z.sup.A --COOH, where Z.sup.A represents an alkylene group having less than 3 carbon atoms or an alkenylene group having less than 3 carbon atoms, and salts, esters and amides thereof have a preventative activity against hyperglycemia and obesity.
European Patent Publication No. 262 785, moreover, discloses that, of the compounds having this formula, 2-[2-(4-carboxymethoxyphenyl)-1(R)-1-methylethyl]amino-1(R)-(3-chloropheny l)ethanol and its methyl ester and pharmaceutically acceptable salts thereof (referred to as the "RR-isomer"), which may optionally contain some proportion of 2-[2-(4-carboxymethoxyphenyl)-1(S)-1-methylethyl]amino-1(S)-(3-chloropheny l)ethanol and its methyl ester and pharmaceutically acceptable salts thereof (the "SS-isomer"), provided that the content of the SS-isomer is not more than 50% by weight of the mixture of RR- and SS-isomers, is particularly effective as an anti-hyperglycemic or anti-obese medicine.
We have now discovered a limited series of novel 2-[2-(substituted phenyl-oxy, thio or methyl)-1-methylethyl]aminoethanol derivatives which have valuable anti-diabetic and anti-obesity activities, with a low toxicity, accompanied by much fewer side effects; the compounds of the present invention, moreover, have the ability to inhibit the action of aldose reductase, and so they can also be effective in the treatment and prevention of complications of diabetes. They are also effective in the treatment and prophylaxis of obesity-related hypertension and osteoporosis.